Exploring differences in response to treatment with peginterferon alpha 2a (40kD) and ribavirin in chronic hepatitis C between genotypes 2 and 3

Article (PDF Available)inJournal of Viral Hepatitis 15(1):52-7 · February 2008with19 Reads
DOI: 10.1111/j.1365-2893.2007.00889.x · Source: PubMed
Abstract
Chronic hepatitis C virus (HCV) infections with genotype 2 or 3 are associated with favourable sustained virologic response (SVR) rates. However, genotype 3 may respond less well. We reassessed all treatment-naive patients with genotype 2 and 3 participating in a large expanded-access, non-randomized, open-label trial, evaluating 180microg pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly and 800 mg/day ribavirin for 24-48 weeks. Factors measured prior to initiation of antiviral therapy were considered in the multiple logistic regression model for predicting SVR. In total, 180 patients were analysed of which 72 (40%) were infected by genotype 2 and 108 (60%) genotype 3. The baseline characteristics between patients infected by genotype 2 or 3 were no different including the distribution of hepatic fibrosis stages by METAVIR score. Overall SVR was lower in those patients infected with genotype 3. The significant multivariate predictors of lack of SVR were hepatic fibrosis (P = 0.014) and genotype 3 (P = 0.030). The negative impact of cirrhosis (METAVIR score F4) on treatment response was more evident among subjects with genotype 3 than those with genotype 2 (P = 0.027). There is significant interaction between cirrhosis and genotype 3 leading to a poor antiviral response in such patients requiring an alternate management strategy. This finding should be confirmed in a larger population.

Figures

Exploring differences in response to treatment with
peginterferon alpha 2a (40kD) and ribavirin in chronic
hepatitis C between genotypes 2 and 3
J. Powis,
1
K. M. Peltekian,
2
S. S. Lee,
3
M. Sherman,
1
V. G. Bain,
4
C. Cooper,
5
M. Krajden,
5
M. Deschenes,
7
R. F. Balshaw,
6
E. Jenny Heathcote
1
and E. M. Yoshida
7
for the Canadian
Pegasys Study Group*
1
Department of Medicine, University of Toronto, Toronto, ON;
2
Department of Medicine, Dalhousie University,
Halifax, NS;
3
Department of Medicine, University of Calgary, Calgary, AB;
4
Department of Medicine, University of Alberta, Edmonton, AB;
5
Department
of Medicine, British Columbia Centre for Disease Control, Vancouver, BC;
6
Department of Medicine, Syreon Corporation, Vancouver, BC; and
7
Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Received January 2007; accepted for publication April 2007
SUMMARY. Chronic hepatitis C virus (HCV) infections with
genotype 2 or 3 are associated with favourable sustained
virologic response (SVR) rates. However, genotype 3 may
respond less well. We reassessed all treatment-naive patients
with genotype 2 and 3 participating in a large expanded-
access, non-randomized, open-label trial, evaluating 180lg
pegylated interferon (peg-IFN) alpha-2a (40kD) once weekly
and 800 mg/day ribavirin for 24–48 weeks. Factors mea-
sured prior to initiation of antiviral therapy were considered
in the multiple logistic regression model for predicting SVR.
In total, 180 patients were analysed of which 72 (40%) were
infected by genotype 2 and 108 (60%) genotype 3. The
baseline characteristics between patients infected by geno-
type 2 or 3 were no different including the distribution of
hepatic fibrosis stages by METAVIR score. Overall SVR was
lower in those patients infected with genotype 3. The sig-
nificant multivariate predictors of lack of SVR were hepatic
fibrosis (P= 0.014) and genotype 3 (P= 0.030). The neg-
ative impact of cirrhosis (METAVIR score F4) on treatment
response was more evident among subjects with genotype 3
than those with genotype 2 (P= 0.027). There is significant
interaction between cirrhosis and genotype 3 leading to a
poor antiviral response in such patients requiring an alter-
nate management strategy. This finding should be confirmed
in a larger population.
Keywords: cirrhosis, genotype, hepatic fibrosis, hepatitis C
virus, interferon therapy, outcomes, sustained viral response.
INTRODUCTION
Antiviral therapy for the treatment of hepatitis C virus (HCV)
infection has evolved over time from interferon monotherapy
to combination therapy with interferon and ribavirin (RBV),
to the present standard of care, namely pegylated interferon
(peg-IFN) and ribavirin [1–7]. Several factors have become
evident as predictors of response to antiviral therapies;
however, none are more powerful than genotype. Genotype
2 and 3 infections are consistently associated with signifi-
cantly higher rates of sustained virological response (SVR)
compared with genotype 1 infections [8–12]. Although the
precise biological explanation for the difference in sustained
virological response (SVR) rates among genotype 1 vs
genotype 2 and 3 remains elusive, it has been clearly dem-
onstrated that viral kinetics in response to interferon therapy
differ between the two groups in both the first and second
phase of viral decline. The viral decline among genotype 2
and 3 infections is up to eight times faster than that of
genotype 1 [13,14]. This rapid virological response to ther-
apy has prompted the development of shorter courses of
therapy for genotype 2 and 3 from the traditional 48 weeks
to as few as 12–16 weeks in investigative protocols, when-
ever a rapid virological response (RVR) is achieved with HCV
polymerase chain reaction (PCR) negativity after 4 weeks of
therapy [9,11,12].
As a result of their favourable antiviral response, genotype
2 and 3 infections are frequently grouped together when the
results of clinical trials are evaluated and hence also in
OnlineOpen: This article is available free online at www.blackwell-synergy.com
Abbreviations: BMI, body mass index; HCV, hepatitis C virus; MLR,
multiple logistic regression; PCR, polymerase chain reaction; peg-
IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virological
response.
Correspondence: Dr E. Jenny Heathcote, 399 Bathurst Street, 6B Fell
Pavilion, Room 154, Toronto, ON, Canada M5T 2S8. Tel: (416) 603-
5914; Fax: (416) 603-6281. E-mail: jenny.heathcote@utoronto.ca
*See Appendix for the Study Group.
Journal of Viral Hepatitis, 2008, 15, 52–57 doi:10.1111/j.1365-2893.2007.00889.x
2007 The Authors
Journal compilation 2007 Blackwell Publishing Ltd
treatment guidelines [9,11,12]. More recent studies,
however, have reported that genotype 3 infections are
associated with lower rates of SVR than genotype 2 infec-
tions in clinical trials of treatment with pegylated interferon
and ribavirin [8,9,11,12]. Although genotype has been a
consistent factor associated with treatment response among
genotype 2 and 3 patients, there is little consensus regarding
other factors associated with differential response between
patients with genotype 2 and genotype 3. Dalgard et al. [9] in a
pilot study of a short course (14 weeks) of therapy with peg-
IFN alpha-2b and RBV demonstrated that the lack of bridging
fibrosis/cirrhosis was an important factor associated with SVR
in a mixed genotype 2/3 cohort of patients. Von Wagner
et al. [12] and Zeuzem et al. [8] found that a high baseline viral
load but not fibrosis was associated with a lack of SVR, espe-
cially among patients with genotype 3 [8,12]. Finally, a study
by Mangia et al. [11] did not identify any factors other than
genotype that predicted response among the study population
consisting primarily of patients with genotype 2.
Response to antiviral therapy is not the only differentiat-
ing characteristic between the two genotypes. Genotype 3
has long been known to be associated with hepatic steatosis
independent of other factors such as body mass index (BMI)
and alcohol intake, whereas no such relationship exists be-
tween hepatic steatosis and genotype 2 [15–18]. Genotype 3
has also been demonstrated to have considerable differences
in E
2
glycoprotein compared with genotype 1, which appears
to preferentially induce apoptosis, possibly promoting hepa-
tic fibrogenesis [19,20]. The most striking evidence demon-
strating the direct impact of genotype 3 infection on
hepatocytes is the reversal of steatosis with successful an-
tiviral therapy [21,22].
Thus genotype 2 and 3 appear to behave differently in the
host as well as in their response to antiviral therapy. The aim
of our study was to confirm the difference in SVR among
genotype 2- and genotype 3-infected HCV patients and
determine factors associated with antiviral response to peg-
IFN alpha-2a and RBV, as well as exploring interactions
between these factors and genotype.
PATIENTS AND METHODS
Study population
This study is a re-analysis of a large Canadian expanded-
access, multi-centred, non-randomized, open-label phase
III-B trial evaluating 180 lg 40-kDa peg-IFN (Pegasys
;
F. Hoffman-La Roche Ltd, Pharamaceuticals Division,
Granzacherstrasse, Basel, Switzerland) once weekly and
800 mg/day RBV (Copegus
; F. Hoffman-La Roche Ltd,
Pharamaceuticals Division, Granzacherstrasse, Basel,
Switzerland) for 24 or 48 weeks for the therapy of chronic
hepatitis C [23,24]. The patients were allocated at the
discretion of the site investigator, to either a planned 24 or
48 weeks with peg-IFN and RBV. At the time of the Canadian
study, the results of Hadziyannis et al. regarding the equiv-
alence of SVR by 24- or 48-week therapy in genotype 2 and 3
had not been published [10]. Our study specifically examined
the differential treatment effect of genotype 2 and 3 infections
in those naı
¨ve to antiviral therapy who underwent at least
12 weeks of therapy. The protocol has been described in
detail elsewhere [23,24]. Briefly, between April 2001 and
June 2004, patients were recruited from 18 sites across
Canada according to standard eligibility criteria which
included positive HCV antibody, positive qualitative
HCV-RNA, lack of co-infection with hepatitis B or human
immunodeficiency virus (HIV), absence of another cause of
liver disease and a liver biopsy within the past year. Liver
biopsy samples were analysed by local expert pathologists
and staged according to the previously validated METAVIR
fibrosis score [25]. In this study, we used stringent definition
of cirrhosis requiring histological finding of regenerative
nodule surrounded by fibrosis (F4 fibrosis score).
Sustained virological response was based on a negative
qualitative HCV PCR result (COBAS Amplicor HCV Test v
2.0; F. Hoffman-La Roche Ltd, Pharmaceuticals Division,
Grenzacherstrasse, Basel, Switzerland) 24 weeks after the
end of the prescribed treatment duration (i.e. 48 weeks in
the 24-week treatment arm and 72 weeks in the 48-week
treatment arm). If HCV PCR testing was not available
24 weeks after completion of treatment, the patient was
declared a treatment failure.
Genotype was determined by the Bayer VERSANT HCV
Genotype Assay (Inno Lipa, Innogenetics, Technologiepark,
Gent, Belgium). All HCV virology analyses were performed at
the British Columbia Centre of Disease Control Virology
Laboratory, Vancouver, BC, Canada.
Statistical analysis
Only factors available prior to the initiation of antiviral
therapy were considered as potential predictors in the anal-
ysis (age, gender, BMI, baseline viral load, genotype and
hepatic fibrosis). Univariate associations between SVR and
categorical predictors were assessed with FisherÕs exact test
(WilcoxonÕs rank-sum test for numeric predictors). Unlike
previous studies, the variables entered into the multiple
logistic regression (MLR) model were analysed as either
continuous or ordinal variables and not grouped into
dichotomous variables. This approach was used, as cut-off
points for variables such as viral load and METAVIR fibrosis
score are not known a priori. Genotype and factors potentially
associated with SVR on univariate analysis (P< 0.15) were
then entered into the MLR model. Thereafter, the differential
influence of predictor variables among genotype was assessed
graphically and if required statistically by modelling the
cross-product of the variable of interest with genotype in an
MLR model. The alpha level of significance for a two-tailed
test was considered to be 0.05. All statistical analyses were
performed using SAS v. 9.1 (SAS Institute, Cary, NC, USA).
2007 The Authors
Journal compilation 2007 Blackwell Publishing Ltd
Chronic hepatitis C: SVR genotype 2 vs 3 53
RESULTS
One hundred and eighty patients met the eligibility criteria.
Baseline data were complete for all patients except for one
(genotype 2) who did not have data for BMI. Baseline
characteristics of the 180 patients are presented in Table 1.
There were 126 (70%) patients assigned to the 24-week
treatment group and 54 (30%) to the 48-week group.
Treatment was discontinued before week 12 in 12 (7%)
patients, five (7%) with genotype 2 and seven (6%) with
genotype 3, because of either poor tolerance or adverse
events. There was no difference among patients infected with
genotype 2 or 3.
Another 12 (7%) patients, three (4%) infected with
genotype 2 and nine (9%) infected with genotype 3, either
dropped out or did not submit a blood sample to the central
laboratory for the final determination of SVR 24 weeks after
completion of therapy. These patients were all considered
treatment failures and assigned to the Ôno SVRÕcategory.
Among the 67 genotype 2 patients who had undergone
at least 12 weeks of therapy, 54 (81%) achieved an
SVR compared with 71 of 101 (70%) genotype 3 patients.
Factors significantly associated with SVR in the whole
cohort of 180 patients on univariate analysis included
METAVIR fibrosis score (P= 0.004), BMI (P= 0.018) and
treatment group (P= 0.033). As shown in Table 2, age,
gender and baseline log viral load were not significant on
univariate analysis.
Genotype, METAVIR fibrosis score, treatment group and
BMI were then assessed in an MLR model with fibrosis score
considered as a categorical variable with values from 0 to 4.
In this initial model, genotype and hepatic fibrosis were the
only independent variables significantly associated with SVR.
The odds ratios associated with lack of SVR are presented in
Table 3. Genotype 3 infections had an overall 2.29 greater
odds for lack of SVR compared with genotype 2 infections,
while a fibrosis score of F3 or F4 compared with F0 had 10.90
and 27.90 greater odds for lack of SVR, respectively. Those
assigned to the 48-week treatment duration also had lower
SVR; however, when the 12 subjects who withdrew early
(before 12 weeks of therapy) were removed from the analysis
this factor lost significance (P= 0.167).
In order to further explore the possibility of an interaction
between genotype and fibrosis, SVR rates were plotted
according to genotype and METAVIR fibrosis score. Figure 1
demonstrates that patients with genotype 3 and cirrhosis
had lower rates of SVR compared with genotype 2 patients
with cirrhosis. Patients with genotype 3 and cirrhosis had an
SVR rate of 17% (2/12) compared with 78% (7/9) among
those with genotype 2 and cirrhosis (P< 0.001; 95% CI for
difference 0.27–0.95). This was assessed statistically by
constructing an MLR model including genotype, cirrhosis
(presence/absence), treatment group and BMI as well as the
cross-product of genotype and cirrhosis. This MLR model
demonstrated that there is a significant interaction between
cirrhosis and genotype, where genotype is an important
Table 1 Characteristics of study popula-
tion according to genotype
Characteristics
Genotype 2
(n= 72)
Genotype 3
(n= 108)
Genotype 2 and 3
(n= 180)
Female 30 (42) 37 (34) 67 (37)
Age (years)
a
48 40 44
BMI (kg/m
2
)
a,b
28 27 27
log
10
viral load (IU/L)
a
5.51 5.82 5.70
METAVIR score
0 5 (7) 14 (13) 19 (11)
1 18 (25) 26 (24) 44 (24)
2 27 (38) 37 (34) 64 (36)
3 13 (18) 19 (18) 32 (18)
4 9 (12) 12 (11) 21 (11)
Treatment duration
24 weeks 45 (62) 81 (75) 126 (70)
48 weeks 27 (38) 27 (25) 54 (30)
Early withdrawal
c
5 (7) 7 (6) 12 (7)
Late drop out
d
3 (4) 9 (9) 12 (7)
Values in parentheses are percentages.
a
Mean.
b
One patient (genotype 2) did not have data of pretreatment BMI available.
c
These patients withdrew before week 12 either due to poor tolerance or adverse
events.
d
These patients dropped out or did not submit blood sample for SVR assessment
24 weeks after completing therapy.
2007 The Authors
Journal compilation 2007 Blackwell Publishing Ltd
54 J. Powis et al.
effect modifier of the negative impact of cirrhosis on response
(P= 0.027). Those patients with genotype 3 and cirrhosis
do worse than those with genotype 2 and cirrhosis. This
difference was not due to adherence as the latter finding
remained intact even when data were reanalysed after
excluding the 12 patients who withdrew early (before
12 weeks of therapy) or the 12 patients who did not submit
a blood sample for determination of SVR 24 weeks after
completing the treatment course.
DISCUSSION
Therapy with peg-IFN alpha 2a and ribavirin 800 mg/day
achieves SVR rates in over 70% when those with genotype 2
and 3 infections are treated as a homogenous group [10].
The remainder either does not respond to antiviral therapy
or relapses after cessation of therapy. This study demon-
strates that there was a significant interaction between cir-
rhosis and genotype 3 infections. The SVR rate among
genotype 2 infections with cirrhosis was 78% compared with
17% among those patients with genotype 3 and cirrhosis.
Our findings show the negative effect on treatment response
of advanced fibrosis, especially cirrhosis, is limited to geno-
type 3 infections with no demonstrable effect on genotype 2.
The influence of hepatic fibrosis on responsiveness to an-
tiviral therapy has been previously demonstrated in one
other clinical trial involving patients with genotype 2 and 3
infections [9]. Other investigators, however, have not found
the same association between hepatic fibrosis and SVR
among genotypes 2 and 3 [8,11,12].
There are several possible explanations for the discrepancy
between our results and those of other trials of peg-IFN for
the treatment of genotype 2 and 3. Similar to the study by
Dalgard et al. [9], more than a quarter of our patients had
advanced fibrosis (17% F3 and 11% F4); this compares well
Table 3 Multivariate analysis of factors associated with lack
of SVR
Variable Odds ratio (95% CI) p-value
Genotype
21
3 2.29 (1.08–4.83) 0.030
METAVIR fibrosis score 0.014
01
1 5.50 (0.63–48.32) 0.124
2 7.58 (0.91–63.19) 0.061
3 10.90 (1.23–96.40) 0.032
4 27.90 (2.93–265.73) 0.004
BMI
a
1.07 (0.99–1.16) 0.102
a
One patient did not have data on BMI available and was not
included in the MLR model.
Table 2 Univariate analysis of factors at baseline potentially
associated with sustained virological response
SVR No SVR p-value
Age (years)
a
44 43 0.595
c
Gender 0.315
d
Female 50 (40) 17 (31)
Male 75 (60) 38 (69)
log
10
viral load (IU/L)
a
5.68 5.75 0.861
c
Genotype 0.248
d
2 54 (43) 18 (33)
3 71 (57) 37 (67)
METAVIR fibrosis score 0.004
d
0 18 (14) 1 (2)
1 33 (26) 11 (20)
2 46 (37) 18 (33)
3 19 (15) 13 (24)
4 9 (7) 12 (22)
BMI (kg/m
2
)
a,b
27 28 0.018
c
Assigned treatment duration
e
0.033
d
24 weeks 94 (75) 32 (58)
48 weeks 31 (25) 23 (42)
Values given in parentheses are percentages.
a
Mean.
b
One patient did not have data available for BMI.
c
Wilcoxon rank-sum test.
d
FisherÕs exact test.
e
When the 12 patients (five from 24-week therapy and seven
from 48-week therapy) who withdrew early (before week
12) due to poor tolerance or adverse events are excluded,
this factor loses its significance (P= 0.167).
001234
10
20
30
40
50
60
70
80
90
100
METAVIR Score
Percent SVR
Genotype 2
Genotype 3
# treated
Genotype 2 5 18 27 13 9
14 26 37 19 12
Genotype 3
Fig. 1 Sustained virological rates according to genotype
and METAVIR fibrosis score There was a significant inter-
action between genotype and cirrhosis (F4) (P= 0.027).
P-value was derived from the cross-product of genotype and
cirrhosis in a multivariate logistic regression model of SVR
including cirrhosis (presence/absence), treatment group,
BMI and genotype.
2007 The Authors
Journal compilation 2007 Blackwell Publishing Ltd
Chronic hepatitis C: SVR genotype 2 vs 3 55
with the 18% F3 plus only 6% F4, and 18% of patients with
METAVIR fibrosis score of 3 in the studies of Zeuzem et al.
[8] and Mangia et al. [11], respectively. In these two studies,
demonstrating an association between baseline viral load
and SVR among genotype 3, the focus was on courses of
therapy of £24 weeks. In the study by Von Wagner et al.
[12], the group treated for 16 weeks with genotype 3 and a
high baseline viral load, had a poorer response.
Most importantly, during the development of our MLR
analysis we did not dichotomize variables such as fibrosis score
and baseline viral load as was done in previously mentioned
studies of patients with genotype 2 and 3. This analytical
approach allowed for improved statistical power and data-
driven exploratory analysis rather than arbitrarily choosing
non-data-driven cut-off points to dichotomize variables.
Our finding of an interaction between genotype and
cirrhosis is limited by the sample size of 21 patients with
cirrhosis in our study. Of course there are problems with
inter-observer variability for the histological scoring of liver
biopsies. This is less of a problem in staging of fibrosis
compared with grading of activity especially with expert
pathologists [26]. However, one would expect that any
variability in identifying cirrhosis would occur equally in
patients with genotype 2 or 3. As the power was robust, it is
unlikely that this represents a type 1 statistical error.
Although our sample size is small, it is larger than the
number of patients with advanced fibrosis in the trials listed
above specifically addressing the treatment of genotype 2
and 3 infections. Because of the published recommendations
suggesting that a pretreatment liver biopsy does not need to
be performed in those patients with genotype 2 and 3 there
is a paucity of data available from other clinical studies to
address the interaction between genotype 3 and fibrosis [27].
Regardless of this, our findings will need to be confirmed in
subsequent studies with a larger population.
The precise pathophysiological mechanism explaining the
difference in SVR among patients with cirrhosis and geno-
type 2 vs genotype 3 is uncertain. Yet this may be explained
in part by the different early viral dynamics between the two
genotypes in response to antiviral therapy, especially among
those with advanced fibrosis. Early decreases in HCV viral
load have been shown by several investigators to be an
independent predictor of subsequent SVR to antiviral agents
[9,28–30]. Hepatic fibrosis has been demonstrated to be
associated with a slowing in the decline in HCV-RNA within
the first 24 h of interferon therapy [31], and lack of fibrosis
is an independent predictor of rapid virological response [9].
Genotype 2 infections are associated with a more rapid, free
virion clearance rate, better inhibition of viral replication
and enhanced killing of HCV-infected cells in response to
IFN therapy [14,31]. Even though a genotype 2-infected
patient may have advanced hepatic fibrosis, the high IFN
sensitivity of genotype 2 may be able to overcome the neg-
ative impact of fibrosis. In comparison, among genotype 3
infections the viral killing in association with antiviral
therapy may not be able to overcome the influence of hepatic
fibrosis.
Current recommendations for the treatment of genotype 2
and 3 infections do not include pretreatment liver biopsy.
The most recent NIH recommendations state that as the
favourable response to current antiviral therapy that occurs
in more than 70% of patients infected with genotype 2 or 3,
it may not always be necessary to perform a liver biopsy
[27]. Our data would support this recommendation for those
with genotype 2 infections, yet in genotype 3 infections a
pretreatment liver biopsy would yield important information
on the patientÕs subsequent response to antiviral therapy
and perhaps question their appropriateness for shorter
courses of therapy. Although rapid virologic response is also
a valuable tool predicting ultimate SVR among genotype 3
patients, it may not alleviate the need for pretreatment liver
biopsy. In order to provide patients with subsequent infor-
mation about the likelihood of achieving a clinical cure, they
need to endure a minimum of 4 weeks of therapy [9,11,12].
In conclusion this study demonstrates an interaction be-
tween genotype and cirrhosis, where patients with genotype
3 and cirrhosis respond less well to therapy than those with
genotype 2 and cirrhosis. If these findings are confirmed in a
larger population, patients with genotype 3 infections may
benefit from pretreatment liver biopsies in order to determine
their degree of hepatic fibrosis and likelihood of subsequent
response to antiviral therapy. Whether patients with geno-
type 3 and advanced fibrosis may benefit from more pro-
longed courses of peg-IFN and ribavirin also needs further
examination.
ACKNOWLEDGEMENTS
J.E.P. is supported by a research fellowship through the
Canadian Institutes for Health Research sponsored National
Canadian Research Training Program in Hepatitis C.
APPENDIX
The Canadian Pegasys Study Group also includes: Frank
Anderson MD, The Liver & Intestinal Research Centre,
Vancouver, BC; Robert Baily MD, Royal Alexandra Hospital,
Edmonton, AB; Curtis Cooper, MD, University of Ottawa,
Ottawa, ON; Marc Deschenes, MD, McGill University, Mon-
treal, QC; Victor Feinman MD, Mount Sinai Hospital, Tor-
onto ON; Susan Greenbloom MD, Toronto Digestive Disease
Associates Inc., Toronto ON; Nir Hilzenrat MD, Montreal
Jewish General Hospital, Montreal QC; Kelly Kaita MD, John
Buhler Research Centre, Winnipeg MB; Paul Marotta MD,
London Health Sciences Centre, London ON; Linda Scully
MD, The Ottawa Civic Hospital, Ottawa ON; Bernard
Willems MD, CHUM Ho
ˆpital Saint. Luc, Montreal QC; Helga
Witt-Sullivan MD, Hamilton Health Sciences Corp-General
Site, Hamilton ON; Lawrence Worobetz MD, Royal Univer-
sity Hospital, Saskatoon, SK.
2007 The Authors
Journal compilation 2007 Blackwell Publishing Ltd
56 J. Powis et al.
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Chronic hepatitis C: SVR genotype 2 vs 3 57
    • "Viral load data were also incomplete, with 40 % or more of patients missing this information at baseline. Previous studies have identified race as a significant risk factor for poor response to treatment due to a higher prevalence of favorable allelic variations at the IL28B promoter in certain ethnic populations [14, 32, 34, 50], and baseline viral load has previously been identified as a predictor of treatment response [7, 11, 13, 14, 30]. Also, a major limitation of the study was the lack of RVR data collected. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this investigation was to assess the real-life effectiveness of pegylated interferon (peg-IFN) α-2b with ribavirin (RBV) in a cohort of treatment-naïve patients with chronic genotypes 2 (G2) or 3 (G3) hepatitis C virus (HCV) infection. A post-hoc pooled analysis of two Canadian multicenter, observational studies, RediPEN and PoWer, was carried out. A total of 1242 G2- or G3-infected patients were included. The primary outcome was sustained virologic response (SVR). Secondary endpoints included early virologic response (EVR), end-of-treatment (EOT) response, and relapse. Multivariate logistic regression was used to identify independent predictors of treatment response. SVR in G2 and G3 was 74.4 % and 63.6 %, respectively. Relapse occurred in 12.7 % and 19.1 % of G2- and G3-infected patients achieving EOT response, respectively. Overall, G3 was found to independently predict reduced SVR [odds ratio (OR) = 0.20; p = 0.007] and increased relapse (OR = 6.84; p = 0.022). Among G3-infected patients, increasing fibrosis score was the most important factor predicting reduced SVR [F2 vs. F0/F1 (OR = 0.41; p = 0.009); F3 vs. F0/F1 (OR = 0.72; p = 0.338); F4 vs. F0/F1 (OR = 0.27; p = 0.001)]. Male gender (OR = 13.16; p = 0.020) and higher fibrosis score [F2 vs. F0/F1 (OR = 9.72; p = 0.016); F3/F4 vs. F0/F1 (OR = 4.23; p = 0.113)] were associated with increased relapse in G3 patients. These results support the real-life effectiveness of peg-IFN α-2b plus ribavirin in HCV G2- and G3-infected patients. Overall, genotype was identified as the most significant predictor of treatment outcome. Fibrosis score and gender were key outcome predictors in the G3-infected population. In clinical settings, peg-INF/RBV offers an alternative for patients without access to all oral direct-acting antivirals.
    Full-text · Article · Feb 2016
    • "More than one fifth of chronically infected HCV patients develop cirrhosis after 20 years of infection [Jablonowska et al., 2012]. The standard treatment for chronic HCV infection is pegylated interferon and ribavirin from 24 to 48 weeks depending upon HCV genotype, which is, however, effective in fewer than 60% of the patients [Powis et al., 2008; Wu et al., 2012]. This therapy may also has adverse effects and the patients often opt for discontinuation of treatment [Rosen and Gretch, 1999]. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to describe the genetic characteristics of Pakistani patients infected with hepatitis C virus (HCV) in relation to IL28B polymorphisms and its association to interferon and ribavirin treatment response. A total of 220 patients, infected with HCV were enrolled, out of which 100 were responders and 120 were nonresponders. The whole blood samples were collected to extract viral RNA and genomic DNA. PCR following the restriction fragment length polymorphism method was used to genotype IL28B rs12979860, rs8099917, and rs12980275 polymorphisms. Liver biopsies and HCV genotyping were performed in nonresponder patients. The rs12980275 AA genotype exhibited significant correlation to treatment response and was found in 62% of the responders and 37.5% of nonresponder patients, whereas AG genotype was noticed frequently in the nonresponder group (P < 0.0001). The rs12979860 CT and rs8099917 TT genotypes were found in 74% and 66% of the responders as compared to 58.3% and 50.8% in nonresponder patients (P = 0.001 and P = 0.032) respectively. HCV 3a genotypes were detected in 50.8% of the nonresponder patients. No significant association was detected between liver biopsy findings and IL28B SNPs (P > 0.05). The results showed the significant association of rs12980275 polymorphism with treatment response in HCV patients followed by rs12979860 and rs8099917. This is the first report describing the association of rs12980275 with response to HCV treatment from Pakistan. These findings may help in predicting the outcome of pegylated interferon and ribavirin treatment in HCV patients, and may reduce the side effects and cost of treatment in predicting non-responder patients. J. Med. Virol. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Feb 2015
    • "These would need to stratify by at least two of the major adverse factors for an SVR, fibrosis stage, and baseline viral load [3] [14], as they can significantly influence the outcome of antiviral therapy. This was shown when re-analyzing the experience of a Canadian multi-centered and non-randomized study in which the rate of SVR in G3 patients with cirrhosis was 17%, in comparison to >60% in the absence of cirrhosis [25]. The ongoing EXACT-R(3) is a randomized clinical trial exploring the benefit of an extended regimen (48-vs 24-week) of pegIFN-a2b, using weight-based RBV, with proper stratification for fibrosis and baseline viral load. "
    [Show abstract] [Hide abstract] ABSTRACT: Genotypes 2 and 3 (G2/G3) of hepatitis C virus have been lumped together as 'easy to treat'. As a result, guidelines recommend 24 weeks of peginterferon/ribavirin for both. However, a closer look at trials shows that these genotypes are not the same, with G2 infection proving more responsive to peginterferon. The data supporting this conclusion are presented along with possible explanations for the differences observed. Ultimately, decisions must be made about therapy. Rapid virological response (RVR) may be the best parameter predicting successful antiviral therapy. For patients with G2 infection who achieve an RVR, shortened courses of therapy are effective. In contrast, for G3 patients without an RVR, there may be benefit to extending therapy to 48 weeks; however, this requires confirmation in prospective studies. Using RVR to guide therapy may level the playing field between these 'easy to treat' genotypes.
    Full-text · Article · Feb 2011
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